Eruptive Nevi Mimicking Wart-Like Lesions under Selective BRAF Inhibition in a 37-Year-Old Female Melanoma Patient.

BACKGROUND: The BRAF inhibitor vemurafenib is state of the art in therapy of patients with malignant melanoma in non-resectable stage III or stage IV and evidence of oncogenetic BRAF mutation. Multiple cutaneous side effects like rash and keratoacanthoma-like lesions have been described so far. CASE REPORT: We report a patient who presented multiple wart-like lesions under therapy with vemurafenib. Histologically we have seen multiple melanocytic nevi with a wart-like appearance. One melanoma in situ developed on the left forearm. CONCLUSIONS: Eruptive nevi and induction of melanoma may be a further side effect in patients undergoing a therapy with BRAF inhibitors.

Oral alitretinoin for the treatment of recalcitrant pityriasis rubra pilaris.

Treatment of pityriasis rubra pilaris is still challenging. We here present a 74-year-old woman who had not experienced stable remission of her skin symptoms during prior treatments including topical and systemic corticosteroids, phototherapy, orally administered acitretin, cyclosporine, methotrexate and adalimumab. A therapy with oral alitretinoin was started and tolerated very well. After a few weeks, skin condition improved significantly and itching and scaling disappeared. The present case shows that alitretinoin might be an alternative in the treatment of recalcitrant pityriasis rubra pilaris type I. Further studies are needed to investigate the benefit of this encouraging result.

Analysis of treatment costs for complex scalp wounds.

BACKGROUND: Two stage reconstructions of deep scalp wounds with exposed calvarial bone require a vital granulation tissue. By evaluating different surgical approaches functional and cosmetic results as well as economic aspects have to be taken into account. PATIENTS AND METHODS: 52 patients undergoing three different surgical procedures for soft tissue reconstruction of complex scalp wounds with exposed bone were included into a retrospective study. All patients underwent a two stage procedure with 3D histologic control, soft tissue reconstruction and final split thickness skin grafting. Soft tissue reconstruction was carried out using allogenic fascia lata, an artificial skin substitute or a negative pressure wound therapy (NPWT). The costs for all used materials as well as personnel and infrastructure were calculated. RESULTS: Comparing the costs for the different treatments, the fascia lata group was least costly (4,475 €) followed by the artificial skin substitute group (4,557 €). The highest expenses occurred in the NPWT group (7,.521 €). The artificial skin substitute group had the fewest dressing changes and the shortest treatment time. CONCLUSIONS: Although dermal regeneration templates are expensive, their use may be economic. NPWT causes high treatment costs due to high daily rental rates and frequent and time-consuming dressing changes.

Inhibitors of Trypanosoma cruzi trypanothione reductase revealed by virtual screening and parallel synthesis.

In an approach to discover new inhibitors of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease, a virtual high-throughput screening was performed. Two structurally new types of inhibitors emerged, the antimicrobial chlorhexidine {1,1'-hexamethylenebis[5-(4-chlorophenyl)biguanide]}, a linear competitive inhibitor (K(i) = 2 +/- 1 microM), and a piperidine derivative acting as mixed inhibitor (K(i) = 6.2 +/- 2 microM and K(i)' = 8.5 +/- 2 microM). Neither compound interferes with human glutathione reductase. Based on chlorhexidine, different series of compounds were synthesized and studied as inhibitors of T. cruzi trypanothione reductase. Most efficient derivatives were three bis(amidines) showing mixed type inhibition with K(i,slope) and K(i,int) values of 2-5 microM and 16-47 microM, respectively. Although these compounds did not exert an improved inhibitory potency compared to chlorhexidine, the change from competitive to mixed-type inhibition is advantageous, since substrate accumulation does not overcome inhibition. Remarkably, all three derivatives carried two copies of an identical 2-methoxy-4-methyl-1-(phenylmethoxy)benzene substituent.

Parasite-specific trypanothione reductase as a drug target molecule.

Trypanosomatids are the causative agents of African sleeping sickness, Chagas' disease, and the different manifestations of leishmaniasis. New drugs against these parasitic protozoa are urgently needed since the current drugs are unsatisfactory, in particular due to serious adverse side effects. In trypanosomes and leishmanias, the nearly ubiquitous glutathione/glutathione reductase system is replaced by trypanothione and trypanothione reductase. The essential role of trypanothione reductase in the parasite thiol metabolism and its absence from the mammalian host render the enzyme a highly attractive target molecule for a structure-based drug development against trypanosomatids. This article provides an overview on the known classes of trypanothione reductase inhibitors and their in vitro activity against parasitic protozoa. The (dis)advantages of the different types of compounds as potential drug candidates as well as modern computer-based approaches to the identification of new leads are discussed.

Coupling of a competitive and an irreversible ligand generates mixed type inhibitors of Trypanosoma cruzi trypanothione reductase.

9-Aminoacridines and (terpyridine)platinum(II) complexes are competitive and irreversible inhibitors, respectively, of trypanothione reductase from Trypanosoma cruzi, the causative agent of Chagas' disease. Four chimeric compounds in which 2-methoxy-6-chloro-9-aminoacridine was covalently linked to the (2-hydroxyethanethiolate)(2,2':6',2' '-terpyridine)platinum(II) complex were synthesized and studied as inhibitors of the parasite enzyme. The derivatives differed by the nature and/or the length of the spacer connecting the two aromatic systems. All four compounds were effective mixed type inhibitors of trypanothione reductase with K(i) and K(i)' values of 0.3-4 and 2-11 microM, respectively. The most potent inhibitor had an ethylthioether linkage between the two aromatic ring systems, and the other compounds contained an alkyl ether group with 4-6 methylene groups. In contrast to the parasite enzyme, human glutathione reductase, the closest related host enzyme was not inhibited by these compounds. The finding that the conjugation of a competitive and an irreversible inhibitor can give rise to reversible mixed type inhibitors underlines the difficulties associated with inhibitor design based on the three-dimensional structure of trypanothione reductase.